Although various peptides have been reported as exhibiting endothelin receptor antagonistic action, there have been reported no non-peptide compounds but anthraquinone derivatives (the official gazette of EP Publication No. 405421 A).
Osteoporosis is a pathologic state or disease involving any symptom or risk due to quantitative reduction in bone exceeding a certain degree. Major symptoms are spinal kyphosis, and fractures of dorsolumbar bone and vertebral centra, femoral neck, lower end of radius, ribs, upper end of humerus, and other bones. In bone tissue, bone destruction occurs constantly with a good balance between bone formation and resorption; osteoblasts and osteoclasts play key roles in bone formation and bone resorption, respectively. If bone resorption surpasses bone formation as a result of the deterioration of the bone destruction balance, a quantitative reduction in bone occurs. Also, inflammatory joint diseases such as chronic rheumatoid arthritis involve accentuated bone resorption, posing a major clinical problem. Drugs suppressing bone resorption are therefore expected to serve well in the prevention and treatment of osteoporosis and inflammatory joint diseases such as chronic rheumatoid arthritis. Traditionally, bone resorption inhibitory agents such as estrogens and calcitonin have been used to treat osteoporosis. To treat inflammatory joint diseases chemotherapeutically, there have been used steroids such as cortisone and other adrenocortical hormones, non-steroidal anti-inflammatory agents such as aspirin, piroxicam and indomethacin, aurothiomalate and other gold agents, antirheumatic agents such as chloroquine preparations and D-penicillamine, anti-gout agents such as colchicine, and immunosuppressants such as cyclophosphamide, azathioprine, methotrexate and levamisole. However, these therapeutic agents fail to have a satisfactory effect in some cases, due to limitation on the subject or to uncertain efficacy. There is therefore a need of a new preventive/therapeutic method for accentuated bone resorption.
It has recently been suggested that cathepsin B, a lysosome cysteine protease, is involved in joint destruction due to inflammatory joint disease [Biochemical Pharmacology, 44, 1201 (1992)]. Also, cathepsin B is thought of as causing intractable muscle collapsing diseases such as myodystrophy and vacuolar distal myopathy. It is also among the enzymes involved in the formation of senile plaques in the brain of patients with Alzheimer's disease. Cathepsin B inhibitors are therefore expected to be useful against these diseases. Traditionally, leupeptin, antipain etc., and epoxysuccinic acid derivatives such as those disclosed in Japanese Patent Unexamined Publication Nos. 304074/1990, 304075/1990 and 304085/1990 are known to exhibit cathepsin B inhibitory action.
On the other hand, among condensed thiadiazole derivatives having a sulfonylimino group are 2-sulfonylimino-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidine and triazine derivatives, which are known to serve as herbicides (see Japanese Patent Unexamined Publication Nos. 263185/1987 and 10795/1988). Also, Japanese Patent Unexamined Publication No. 246389/1985 describes a 2-sulfonylimino-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidine derivative, a compound exhibiting platelet aggregation inhibitory and cardiotonic actions, represented by the following formula: ##STR3## wherein R represents a lower alkyl group or a phenyl group which may be substituted by a lower alkyl group or halogen. However, none of these reports discloses endothelin receptor antagonistic action, cathepsin B inhibiting action and bone resorption inhibitory action.